Beyond erythropoiesis-stimulating agents: The evolving role of hypoxia-inducible factor stabilizers in anemia of chronic kidney disease

Anemia is one of the most common complications affecting individuals with chronic kidney disease (CKD). It is driven primarily by relative erythropoietin (EPO) deficiency, chronic inflammation, and altered iron metabolism. Emerging therapies, known as hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), offer a novel oral treatment approach by stabilizing intracellular HIF levels to mimic tissue hypoxia and stimulate endogenous EPO production. This comprehensive narrative review synthesizes literature indexed in PubMed, MEDLINE, Scopus, and Web of Science to evaluate the efficacy of HIF stabilizers in the anemia of CKD compared to current guideline-directed therapies worldwide. Phase 3 clinical trials consistently demonstrate that HIF-PHIs are non-inferior to conventional erythropoiesis-stimulating agents (ESAs) and superior to placebo in increasing and maintaining hemoglobin levels in both dialysis-dependent and non-dialysis-dependent CKD patients. Additionally, HIF-PHIs improve iron mobilization and utilization by decreasing hepcidin levels. However, trials have raised safety concerns regarding cardiovascular outcomes, including major adverse cardiovascular events, and an increased incidence of thromboembolic events, particularly in non-dialysis-dependent populations. These safety signals have led to divergent global regulatory pathways, with the United States Food and Drug Administration largely restricting approvals to dialysis-dependent patients, while agencies in Europe and Japan have granted broader authorizations. As a growing body of literature accumulates, HIF-PHIs offer a promising oral alternative to ESAs that addresses both relative EPO deficiency and iron sequestration. While they have the potential to become a new standard of care, therapy initiation requires individualized risk-benefit assessments, and continued post-marketing surveillance is necessary to fully elucidate long-term cardiovascular and thromboembolic risks.